Synthesis process of topramezone

Abstract

The invention discloses a synthesis process of topramezone, which is characterized in that 3-(3-bromo-2-methyl-6-methylsulfonyl phenyl)-4, 5-dihydroisoxazole and 1-methyl-5-hydroxypyrazole are used as initial raw materials, and in the presence of introduced CO gas and a mixed catalyst, the topramezone is synthesized through a carbonyl insertion reaction; wherein the mixed catalyst contains an iron-carbon catalyst and other catalysts, and the other catalysts at least comprise a palladium catalyst. According to the synthesis process, sylvite is not used, a small amount of iron-carbon catalyst is introduced as a part of the mixed catalyst, the product yield and the product content of topramezone are remarkably improved, the operation process is simplified, the synthesis cost is reduced, waste discharge is reduced, and the synthesis process is a novel topramezone synthesis process which is higher in yield, more economical and more environmentally friendly.

Description

Technical Field

[0001] The present application belongs to the technical field of pesticide synthesis, and specifically relates to a synthesis process of fenpyrotone. Background Art

[0002] Topramezone, chemical name: 4-[3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-methylsulfonyl]-1-methyl-5-hydroxy-1H-pyrazole, CAS No.: 210631-68-8, molecular formula: C 16 H 17 N 3 O 5 S, the structural formula is as follows:

[0003]

[0004] Benthiocarb is a new type of triketone post-emergence stem and leaf treatment herbicide. It is a para-hydroxyphenylpyruvate dioxidase (HPPD) inhibitor. It inhibits the biosynthesis of plastoquinone and carotenoids, disrupts the synthesis and function of chloroplasts, causes weeds to bleach and eventually die.

[0005] At present, the conventional synthesis process of fenpyroxetine can refer to the Chinese patent application with publication number CN101113137A. The product yield in this scheme is relatively low. For example, in Example 8 of this scheme, it can be seen that the highest yield is only 85.6%, which leads to high cost and large amount of corresponding waste. In addition, this scheme emphasizes the use of potassium salt, especially potassium carbonate, preferably at least 1 molar equivalent, and particularly preferably 2 molar equivalents of potassium salt [based on the intermediate 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole], otherwise the reaction rate will be reduced, or the intermediate Fries rearrangement reaction will not be carried out thoroughly enough, and O-acylated pyrazole derivatives will be generated. The potassium salt must be dried at at least 150°C before use, and after the reaction is completed, there is an additional potassium salt recovery step, which not only causes cumbersome operation, but also wastes energy, etc., which further increases the product cost. From the above, it can be seen that in the solution of the Chinese patent application with publication number CN101113137A, potassium salt needs to be used, and the process is complicated. It needs to be dried before use, and the potassium salt needs to be recovered after the reaction.

[0006] Although there are many improved synthesis processes for benomyl at present, these processes do not significantly improve the content and yield of the final product benomyl. Summary of the invention

[0007] In view of this, the primary purpose of the present application is to provide a synthesis process of benzathine, which does not use potassium salt and adds a small amount of iron-carbon catalyst, which not only optimizes the synthesis process and simplifies the operation process, but also significantly improves the product yield and product content, while reducing the amount of waste and types of pollutants, so that the overall cost of the product has been greatly reduced. In short, the synthesis process of the present application provides a lower cost, more economical and more environmentally friendly industrial process for synthesizing benzathine.

[0008] In order to achieve the above objectives, this application adopts the following technical solutions:

[0009] The present application provides a synthesis process of fenpyrazone, wherein 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole and 1-methyl-5-hydroxypyrazole are used as starting materials, and fenpyrazone is synthesized by carbonyl insertion reaction in the presence of CO gas and a mixed catalyst.

[0010] The mixed catalyst contains an iron-carbon catalyst and other catalysts, and the other catalysts at least include a palladium catalyst.

[0011] The specific synthesis process route is as follows:

[0012]

[0013] In the present application, on the basis of the original traditional process, potassium salt is not used, but a small amount of iron-carbon catalyst is mixed, and after experimental verification, the product content and yield of benzathine chlorpyrifos obtained by the synthesis process of the present application are significantly improved, and because potassium salt is not used, the recovery process of complicated pre-treatment drying process and subsequent potassium salt is omitted. In addition, the catalyst in the present application can be recycled and reused directly after fresh solvent washing, and the recovery process is simple, which can greatly save costs. In general, the synthesis process has higher economic value, and content and yield are significantly improved, which is very suitable for industrial production.

[0014] Among them, in the synthesis process, the ratio of each raw material component can be determined by known experimental methods as needed. Those skilled in the art have such ability. In some examples, the ratio of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxane, 1-methyl-5-hydroxypyrazole, iron-carbon catalyst and other catalysts is 1 mol: 1 mol: 6-6.5 g: 0.04-0.05 mol.

[0015] In the present application, the other catalysts described may be palladium catalysts only, or may be a mixture of palladium catalysts and phosphine ligands. The use of palladium catalysts is a relatively conventional process in the art, and those skilled in the art may select them according to actual conditions.

[0016] In some examples, the other catalyst is a palladium catalyst, and the palladium catalyst is bis(triphenylphosphine)palladium dichloride or tetrakis(triphenylphosphine)palladium, preferably bis(triphenylphosphine)palladium dichloride.

[0017] In other examples, the other catalyst is a mixture of a palladium catalyst and a phosphine ligand. Wherein, the palladium catalyst is palladium chloride or palladium acetate, and the phosphine ligand is at least one of triphenylphosphine, tributylphosphine, and tricyclohexylphosphine; preferably, the palladium catalyst is palladium chloride, and the phosphine ligand is triphenylphosphine. Wherein, the palladium catalyst and the phosphine ligand can be used in a ratio well known in the art, or determined by a known experimental method. In some specific embodiments of the present application, the molar ratio of the palladium catalyst to the phosphine ligand is 1: (2 to 2.2), and preferably, the molar ratio of the palladium catalyst to the phosphine ligand is 1: 2.

[0018] In a further embodiment, the pressure of the CO gas and the parameters of the carbon insertion reaction are conventional parameters in the art. In some examples, the pressure of the CO gas is 6 kg / cm 2 ~20kg / cm 2 ; The temperature of the carbon insertion reaction is 120-130°C, and the reaction time is 24-48h.

[0019] In addition, it is understood that the carbon insertion reaction also includes solvents and acid binding agents known to those skilled in the art, and those skilled in the art can select them as needed. In some examples, the solvent is acetonitrile or 1,4-dioxane, and the acid binding agent is triethylamine, but it is not limited thereto. The specific amount can be selected as needed without special requirements.

[0020] In a further solution, after the reaction is completed, the mixed catalyst can be directly used after being rinsed with a fresh solvent. The recovery process is simple, the operation is convenient, and the recovery efficiency is high, which has a significant cost advantage.

[0021] In a further scheme, after the reaction is completed, the reactants need to undergo extraction, washing, drying and other processes, which are conventional treatment methods in the art without special limitations. In some examples, the aqueous phase in the reactants is extracted with dichloromethane to remove impurities, and then the aqueous phase is adjusted to a pH of 1 to 2 with 35% hydrochloric acid, filtered, and the filter cake is washed with water and dried to obtain the product benzathine.

[0022] Beneficial effects of this application:

[0023] The synthesis process of benzathine provided in the present application does not use potassium salt, but introduces a small amount of iron-carbon catalyst as part of the mixed catalyst, so that the product yield and product content of benzathine are greatly improved. At the same time, since potassium salt is not used, the post-treatment steps of drying before use and recovering potassium salt after reaction can be reduced, thereby simplifying the operation process, reducing the amount of waste and types of pollutants, and greatly reducing the overall cost of the product.

[0024] In general, the synthesis process of fenpyrotone in the present application reduces the synthesis cost and is a more economical and environmentally friendly industrial process. DETAILED DESCRIPTION

[0025] The following are specific embodiments of the present application. It should be noted that the following specific embodiments are only for illustrative purposes and do not limit the scope of the present application in any way.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0027] In addition, unless otherwise specified, methods without specific conditions or steps are conventional methods, and the reagents and materials used are all commercially available.

[0028] Example 1

[0029] This embodiment provides a synthesis process of fenpyroxetine, and the specific steps are as follows:

[0030] Into a 2 L autoclave were added 1.2 L of acetonitrile, 50 g (0.157 mol) of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole, 15.4 g (0.157 mol) of 1-methyl-5-hydroxypyrazole, 32.5 g (0.32 mol) of triethylamine, 1 g of iron-carbon powder and 5.6 g (0.008 mol) of bis(triphenylphosphine)palladium dichloride.

[0031] The autoclave was sealed and evacuated to -0.1 MPa. The autoclave was then replaced with nitrogen twice and evacuated to -0.1 MPa again. CO gas was introduced to a pressure of 15 kg / cm 2 The mixture was heated to 130°C while stirring. The CO gas pressure was increased to 20 kg / cm 2 And the mixture was stirred at 130°C for 24h.

[0032] After the reaction is completed, the mixed catalyst is filtered and recovered (after washing with a fresh solvent, it can be directly used), the filtrate is concentrated under reduced pressure and the residue is dissolved in water. The aqueous phase is extracted with dichloromethane to remove impurities. The aqueous phase is adjusted to a pH of 1-2 with 35% hydrochloric acid, filtered, the filter cake is washed with water three times, and dried under reduced pressure at 60°C to obtain 54.3 g of the product benzathine, with a content of 97.0% and a yield of 92.3%.

[0033] Example 2

[0034] This embodiment provides another synthesis process of benzathine, and the specific steps are as follows:

[0035] Into a 2 L autoclave were added 1.2 L of 1,4-dioxane, 50 g (0.157 mol) of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole, 15.4 g (0.157 mol) of 1-methyl-5-hydroxypyrazole, 32.5 g (0.32 mol) of triethylamine, 1 g of iron carbon powder, 0.27 g (0.0015 mol) of palladium (II) chloride and 0.82 g (0.0031 mol) of triphenylphosphine.

[0036] The autoclave was sealed and evacuated to -0.1 MPa. The autoclave was then replaced with nitrogen twice and evacuated to -0.1 MPa again. The mixture was heated to 130°C under stirring and CO gas was introduced to a pressure of 6 kg / cm 2 Continuously introduce CO gas to stabilize the CO gas pressure at 6kg / cm 2 And the mixture was stirred at 130°C for 36h.

[0037] After the reaction is completed, the mixed catalyst is filtered and recovered (after washing with a fresh solvent, it can be directly used), the filtrate is concentrated under reduced pressure and the residue is dissolved in water. The aqueous phase is extracted with dichloromethane to remove impurities. The aqueous phase is adjusted to a pH of 1-2 with 35% hydrochloric acid, filtered, the filter cake is washed three times with water, and dried under reduced pressure at 60°C to obtain 54.1 g of the product benzathine, with a content of 97.1% and a yield of 92.1%.

[0038] Example 3

[0039] This embodiment provides another synthesis process of benzathine, and the specific steps are as follows:

[0040] Into a 2L autoclave were added 1.2L of acetonitrile, 50g (0.157mol) of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole, 15.4g (0.157mol) of 1-methyl-5-hydroxypyrazole, 32.5g (0.32mol) of triethylamine, the recovered mixed catalyst in Example 2 (iron-carbon recovery rate greater than 95%, palladium metal recovery rate greater than 90%), 0.01g of palladium (II) chloride and 0.82g (0.0031mol) of triphenylphosphine.

[0041] The autoclave was sealed and evacuated to -0.1 MPa. The autoclave was then replaced with nitrogen twice and evacuated to -0.1 MPa again. CO gas was introduced to a pressure of 15 kg / cm 2 The mixture was heated to 130°C while stirring. The CO gas pressure was increased to 20 kg / cm 2 The mixture was stirred at 130°C for 24h. After the reaction was completed, the mixed catalyst was filtered and recovered (after washing with a fresh solvent, it can be directly used), the filtrate was concentrated under reduced pressure and the residue was dissolved in water. The aqueous phase was extracted with dichloromethane to remove impurities. The aqueous phase was adjusted to a pH of 1-2 with 35% hydrochloric acid, filtered, the filter cake was washed with water three times, and dried under reduced pressure at 60°C to obtain 54.2g of the product benzathine, with a content of 97.2% and a yield of 92.3%.

[0042] Comparative Example 1

[0043] This comparative example provides another synthesis process of benzathine, and the specific steps are as follows:

[0044] Into a 2 L autoclave were added 1.2 L of acetonitrile, 50 g (0.157 mol) of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole, 15.4 g (0.157 mol) of 1-methyl-5-hydroxypyrazole, 32.5 g (0.32 mol) of triethylamine, 44.2 g (0.32 mol) of potassium carbonate and 5.6 g (0.008 mol) of bis(triphenylphosphine)palladium dichloride.

[0045] The autoclave was sealed and evacuated to -0.1 MPa. The autoclave was then replaced with nitrogen twice and evacuated to -0.1 MPa again. CO gas was introduced to a pressure of 15 kg / cm 2 The mixture was heated to 130°C while stirring. The CO gas pressure was increased to 20 kg / cm 2 And the mixture was stirred at 130°C for 24h.

[0046] After the reaction is completed, the catalyst and potassium salt are filtered and recovered (a solid mixture of potassium salt and catalyst is stirred with water, filtered and the catalyst is recovered, and the filtrate is evaporated to recover the mixed potassium salt), the filtrate is concentrated under reduced pressure and the residue is dissolved in water. The aqueous phase is extracted with dichloromethane to remove impurities. The aqueous phase is adjusted to a pH of 1-2 with 35% hydrochloric acid, filtered, and the filter cake is washed with water three times and dried under reduced pressure at 60°C to obtain 49.4 g of the product benzathine, with a content of 95.2% and a yield of 82.4%.

[0047] Comparative Example 2

[0048] This comparative example provides another synthesis process of benzathine, and the specific steps are as follows:

[0049] Into a 2 L autoclave were added 1.2 L of 1,4-dioxane, 50 g (0.157 mol) of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole, 15.4 g (0.157 mol) of 1-methyl-5-hydroxypyrazole, 32.5 g (0.32 mol) of triethylamine, 44.2 g (0.32 mol) of potassium carbonate, 0.27 g (0.0015 mol) of palladium (II) chloride and 0.82 g (0.0031 mol) of triphenylphosphine.

[0050] The autoclave was sealed and evacuated to -0.1 MPa. The autoclave was then replaced with nitrogen twice and evacuated to -0.1 MPa again. The mixture was heated to 130°C under stirring and CO gas was introduced to a pressure of 6 kg / cm 2 Continuously introduce CO gas to stabilize the CO gas pressure at 6kg / cm 2 And the mixture was stirred at 130°C for 36h.

[0051] After the reaction is completed, the catalyst and potassium salt are filtered and recovered (a mixture of potassium salt and catalyst solids is stirred with water, filtered and the catalyst is recovered, and the filtrate is evaporated to recover the mixed potassium salt), the filtrate is concentrated under reduced pressure and the residue is dissolved in water. The aqueous phase is extracted with dichloromethane to remove impurities. The aqueous phase is adjusted to a pH of 1-2 with 35% hydrochloric acid, filtered, and the filter cake is washed with water three times and dried under reduced pressure at 60°C. The product 48.7g of benzathine is obtained, with a content of 95.0% and a yield of 81.1%.

[0052] It can be seen from the above examples and comparative examples that the present application not only optimizes the synthesis process and simplifies the operation, but also improves the product content and yield of benomyl, which has significant advantages.

[0053] It should be noted that the present application is not limited to the above-mentioned embodiments. The above-mentioned embodiments are only examples, and the embodiments having the same structure as the technical idea and exerting the same effect within the scope of the technical solution of the present application are all included in the technical scope of the present application. In addition, without departing from the scope of the main purpose of the present application, various modifications that can be thought of by those skilled in the art to the embodiments and other methods of combining some of the constituent elements in the embodiments are also included in the scope of the present application.

Claims

1. A synthesis process of fenpyrazone, characterized in that: The synthesis process uses 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole and 1-methyl-5-hydroxypyrazole as starting materials, and synthesizes fenpyrazone through carbonyl insertion reaction in the presence of CO gas and a mixed catalyst. The mixed catalyst contains an iron-carbon catalyst and other catalysts, and the other catalysts at least include a palladium catalyst.

2. The synthesis process of fenpyrazone as claimed in claim 1, characterized in that: In the synthesis process, the ratio of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxane, 1-methyl-5-hydroxypyrazole, iron-carbon catalyst and other catalysts is 1 mol: 1 mol: 6-6.5 g: 0.04-0.05 mol.

3. The synthesis process of fenpyrazone as claimed in claim 1, characterized in that: The other catalyst is a palladium catalyst, and the palladium catalyst is bis(triphenylphosphine)palladium dichloride or tetrakis(triphenylphosphine)palladium.

4. The synthesis process of fenpyrazone as claimed in claim 1, characterized in that: The other catalyst is a mixture of a palladium catalyst and a phosphine ligand.

5. The synthesis process of fenpyrazone as claimed in claim 4, characterized in that: The palladium catalyst is palladium chloride or palladium acetate, and the phosphine ligand is at least one of triphenylphosphine, tributylphosphine and tricyclohexylphosphine.

6. The synthesis process of fenpyrazone as claimed in claim 4 or 5, characterized in that: The molar ratio of the palladium catalyst to the phosphine ligand is 1:(2-2.2).

7. The synthesis process of fenpyrazone as claimed in claim 1, characterized in that: The pressure of the CO gas is 6 kg / cm 2 ~20kg / cm 2 .

8. The synthesis process of fenpyrazone as claimed in claim 1, characterized in that: The temperature of the carbon insertion reaction is 120-130° C., and the reaction time is 24-48 hours.

9. The synthesis process of fenpyrazone as claimed in claim 1, characterized in that: After the reaction is completed, the mixed catalyst can be directly used after being rinsed with a fresh solvent.

10. The synthesis process of fenpyrazone as claimed in claim 1, characterized in that: After the reaction is completed, the aqueous phase in the reactant is extracted with dichloromethane to remove impurities, and then the aqueous phase is adjusted to a pH value of 1-2 with 35% hydrochloric acid by mass, filtered, and the filter cake is washed with water and dried to obtain the product benzathine.

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